N6022 is a selective and reversible inhibitor of S-nitrosoglutathione reductase (GSNOR), with an IC₅₀ of 8nM and a Kᵢ of 2.5nM[1-2]. N6022 exhibits multiple biological functions by binding to the GSNO substrate-binding pocket, thereby increasing intracellular levels of S-nitrosoglutathione (GSNO) and modulating protein S-nitrosylation signaling pathways[3-4].
In vitro, in an oxygen-glucose deprivation/reperfusion (OGD/R) model using BV2 microglial cells, treatment with N6022 (1–10μM) at the onset of reperfusion for 22 hours significantly enhanced cell viability, attenuated the decline in mitochondrial membrane potential, reduced the expression of the pro-apoptotic protein BAX, and upregulated the expression of Bcl-2[5]. In murine myoblast C2C12 cells treated with N6022 (200μM) for 72 hours, N6022 markedly increased mitochondrial numbers and induced the accumulation of endoplasmic reticulum vesicles[6].
In vivo, in a C57BL/6J mouse model of acetaminophen (APAP)-induced acute liver injury, intraperitoneal administration of N6022 (5mg/kg) at 2 hours post-APAP injection significantly reduced serum levels of liver injury markers AST and ALT, alleviated hepatic necrosis and apoptosis, and suppressed the expression of inflammatory factors[7]. In a spinal cord injury (SCI) model in C57BL/6J mice, N6022 (5mg/kg) was administered via tail vein injection starting at 2 hours post-injury and continued for 4 weeks. N6022 significantly improved motor function (as assessed by BMS scores), reduced pain-like behaviors, and ameliorated depressive-like behaviors[8].
References:
[1] Sun X, Qiu J, Strong SA, et al. Structure-activity relationships of pyrrole based S-nitrosoglutathione reductase inhibitors: pyrrole regioisomers and propionic acid replacement. Bioorg Med Chem Lett. 2011 Jun 15;21(12):3671-5.
[2] Colagiovanni DB, Drolet DW, Langlois-Forget E, et al. A nonclinical safety and pharmacokinetic evaluation of N6022: a first-in-class S-nitrosoglutathione reductase inhibitor for the treatment of asthma. Regul Toxicol Pharmacol. 2012 Feb;62(1):115-24.
[3] Blonder JP, Mutka SC, Sun X, et al. Pharmacologic inhibition of S-nitrosoglutathione reductase protects against experimental asthma in BALB/c mice through attenuation of both bronchoconstriction and inflammation. BMC Pulm Med. 2014 Jan 10;14:3.
[4] Khan M, Kumar P, Qiao F, et al. Targeting GSNOR for functional recovery in a middle-aged mouse model of stroke. Brain Res. 2020 Aug 15;1741:146879.
[5] Duan WL, Ma YP, Wang XJ, et al. N6022 attenuates cerebral ischemia/reperfusion injury-induced microglia ferroptosis by promoting Nrf2 nuclear translocation and inhibiting the GSNOR/GSTP1 axis. Eur J Pharmacol. 2024 Jun 5;972:176553.
[6] Li J, Wu W, Ji G, et al. L-NAME improves the morphology and necrosis of skeletal muscle by activating PINK1-PARKIN mediated mitophagy in mdx mice. Brain Dev. 2025 Aug;47(4):104388.
[7] Cui Q, Jiang T, Xie X, et al. S-nitrosylation attenuates pregnane X receptor hyperactivity and acetaminophen-induced liver injury. JCI Insight. 2024 Jan 23;9(2):e172632.
[8] Khan M, Qiao F, Islam SMT, et al. GSNOR and ALDH2 alleviate traumatic spinal cord injury. Brain Res. 2021 May 1;1758:147335. doi: 10.1016/j.brainres.2021.147335.
N6022是选择性且可逆的S-亚硝基谷胱甘肽还原酶（GSNOR）抑制剂，IC50为8nM，Ki为2.5nM[1-2]。N6022具有多种生物学功能，N6022通过结合GSNO底物结合口袋，从而增加细胞内S-亚硝基谷胱甘肽（GSNO）的水平，进而调节蛋白质S-亚硝基化信号通路发挥作用[3-4]。
在体外，在氧糖剥夺/再灌注（OGD/R）BV2小胶质细胞模型中，N6022（1–10μM）于再灌注时处理细胞并培养22小时，N6022能显著提高细胞活力，减轻线粒体膜电位下降，并减少细胞凋亡相关蛋白BAX的表达，同时上调Bcl-2的表达[5]。N6022（200μM）处理小鼠成肌细胞C2C12细胞72小时，N6022显著增加细胞内线粒体数量并诱导内质网囊泡积聚[6]。
在体内，在乙酰氨基酚（APAP）诱导的急性肝损伤C57BL/6J小鼠2小时后，N6022（5mg/kg）腹腔注射给药，显著降低了肝损伤标志物AST和ALT的血清水平，减轻了肝组织坏死和细胞凋亡，并抑制了炎症因子的表达[7]。N6022（5mg/kg）通过尾静脉注射，在C57BL/6J小鼠脊髓损伤（SCI）后2小时开始给药，持续治疗4周。N6022显著改善脊髓损伤后的运动功能（BMS评分）、减轻疼痛样行为和抑郁样行为[8]。